The mammalian intestine is colonised by several hundred bacterial species whose numbers increase dramatically in the colon, an anatomical site prone to infection, inflammatory disease and cancer. However, the resident flora of the gastrointestinal tract of adult-animals conveys a high degree of protection (colonisation resistance) against infection (van der Waaij, 1984; Salminen et al, 1998). As a result, most opportunistic pathogens encountered in the environment are unable to establish a foothold and are rapidly excluded (van der Waaij, 1984; Salminen et al, 1998). However, if the commensal flora is compromised, opportunistic pathogens may then persist in the gut. For example, Pseudomonas aeruginosa does not usually persist in the murine gut but will colonise and cause very severe infection after disruption of the commensal flora with antibiotics (Pier et al, 1992). The commensal bacteria also confer some degree of protection against virulent pathogens, such as Salmonella. However, these pathogens can overwhelm or circumvent the protective effects of the commensal flora and cause severe infection if they are present in significant numbers.
Colonisation resistance is due, in part, to competitive exclusion of harmful bacteria, through preferential use of nutrients and substrates or blocking of potential attachment sites on the gut by the commensal flora. However, commensal bacteria also modulate the gut cellular and immune systems of the host (Bry et al, 1996; Herias et al, 1998; 1999; Hooper et al, 2000; 2001; Cebra, 1999; Snel et al, 1998; Talham et al, 1999; Lopez-Boado et al, 2000; Shu et al, 2000; Campbell et al, 2001). The flora may alter the gastrointestinal tract to create niche microenvironments that are well suited to them but not to other bacteria. Alternatively, they may modify epithelial cell responses to harmful bacteria (Campbell et al, 2001) and thereby attenuate changes that would facilitate colonisation and invasion.
The healthy gut maintains a hyporesponsive tone towards its diverse bacterial load, yet the presence of a threshold level of pathogenic bacteria is sufficient to activate transcriptional systems that rapidly upregulate proinflammatory gene expression in gut tissues. These transcription products then trigger a cascade of responses including the chemotaxis of polymorphonuclear (PMN) cells into the lamina propria of infected intestinal sites. Although these events are essential for bacterial clearance, they also cause tissue pathology that can exacerbate the symptoms of disease. The first point of contact for lumenal bacteria is a continuous layer of ephithelial cells that both interfaces and segregates the gut immune system. The ability of intestinal epithelial cells to discriminate between pathogenic and non-pathogenic bacteria is crucial in averting harmful inappropriate responses to colonising bacteria and in maintaining gut health. This discriminatory function is imprinted in the systems of bacterial recognition and cell signalling. Recognition of bacterial cell surface structures is, in part, a function of Toll-like receptors expressed on apical and basolateral surfaces of epithelial cells, which trigger Nuclear Factor Kappa B (NF-κB)-mediated immune activation (Gerwirtz et al, 2001). Hitherto, receptor systems linked to immune-suppressor activities have not been identified.
Administration of the human commensal bacterium B. thetaiotaomicron to germ-free mice triggered expression of key genes linked to intestinal maturation and development of barrier function (Hooper et al, 2001). It also increased intestinal levels of Fucα1,2Galβ-glycans (Bry et al, 1996; Hooper et al, 2001) and matrilysin (Lopez-Boado et al, 2000). B. thetaiotaomicron was also found to modify the responses of epithelial cells to challenge in vitro with Salmonella (Campbell et al, 2001). In particular, there was suppression of some pro-inflammatory pathways (Campbell et al, 2001). Despite these potentially protective properties, B. thetaiotaomicron did not however increase the resistance of ex-germ free mice to infection by Clostridium perfringens serotype A (Yurdusev et al, 1989). Nonetheless, the pathogen was cleared from the gut if the mice were treated with B. thetaiotaomicron in combination with Fusobacterium necrogenes (Yurdusev et al, 1989) and non-pathogenic Clostridia strain CI (Yurdusev et al, 1986). This suggests that, although B. thetaiotaomicron alone can induce potentially protective changes in the gut, it may need to act in tandem with other commensal strains to significantly enhance overall resistance to infection.